ICH E17 Guideline regions. For example, pooling Canada and the United States into a North American re- gion is often justified because of similar medical practices and similar use of concomitant medications. Pooling strategies should be specified in the study protocol and statistical analysis plan, if applicable. As discussed earlier, region is often a surrogate for the underlying intrinsic and extrinsic factors that tend to differentiate regions or populations from each other.
If there is suffi- cient knowledge about these factors at the trial design stage, it may be possible to define subpopulations based on those factors, and then incorporate these newly defined subpop- ulations in the stratification and analysis, in addition to region. Formally, the term pooled subpopulation refers to pooling of a subset of the subjects from one region with similarly defined subsets from other regions whose members share one or more intrinsic or extrin- sic factors important for the drug development programme. Ethnicity usually crosses regional boundaries and can be an important risk factor for the disease or related to treatment response (as the example in Section 2.2.1.
Figure 2b illus- trates). Pooling ethnic subpopulations across regions in an MRCT provides an oppor- tunity to evaluate the impact of ethnicity on treatment effects. Examples include Hispan- ics living in North and South America, or Caucasians living in Europe and North Amer- ica. Pooling across regional boundaries by other intrinsic or extrinsic factors may also be considered (e.g., by genotype). The sample size allocation should consider the planned analysis of variability of treatment effect among pooled subpopulations, and the principles described above for allocation to regions may also apply to pooled subpopulations.
Note that information about the extrin- sic and intrinsic factors used to define pooling strategies should be collected for subjects enrolled in the trial to be able to monitor the recruitment strategy and ensure adequate regional and subpopulation representation. Other Sample Size Considerations The factors that influence sample size and sample size allocation should be agreed upon in advance with the different regulatory agencies governing the regions represented in the trial. For non-inferiority or equivalence trials, regulatory agreement is also needed on the 17